The proposed research focuses on the development of novel therapeutic agents for the prevention and treatment of malaria caused by P. falciparum. A previous Phase I project has discovered novel molecules with potent antimalarial activity against both sensitive and multidrug resistant malaria strains in some in vitro and in vivo models. Lead compounds are low in toxicity and possess high oral bioavailability. The potential for development of resistance was confirmed to be small and a scalable chemical synthesis was also established. The current SBIR Phase II research was designed after pre-IND meeting with FDA. Under Phase II support, the two lead compounds will be synthesized on a large scale. Range-finding toxicity, repeat dose toxicity, and pharmacokinetic studies will be conducted in monkey models. Antimalarial efficacy will be evaluated in Aotus monkeys infected with P. falciparum. One compound with desired toxicity, efficacy, and pharmacokinetic properties will be selected for cGMP manufacturing. This compound will then undergo GLP toxicology studies: definitive 28-day toxicity study with toxicokinetic, functional observations battery and micronucleus evaluations. An investigational new drug (IND) application will be filed with FDA at the end of Phase II research. The novelty of the project is the discovery of new molecular entities. The project involves standard approaches to drug development, but the multidisciplinary team and multi- institution collaboration that has been assembled will accelerate the generation of clinical candidates.